Up-regulation of IAPs by PI-3K: a cell survival signal-mediated anti-apoptotic mechanism.
Under normal cell physiology, a balance between cell survival and apoptosis is crucial for homeostasis. Many studies have demonstrated that apoptosis is modulated by cell survival stimuli. Active Akt, a common mediator of cell survival signals, has been shown to inhibit apoptosis by attenuating activity of pro-apoptotic factors Bad and caspase-9. However, the anti-apoptotic mechanisms mediated by various cell survival signals are poorly understood. Human prostate cancer LNCaP cells, known to contain constitutively activated Akt as a result of a frame-shift mutation in PTEN, an inhibitor of PI-3K/Akt pathway, were observed to be completely resistant to TRAIL-induced apoptosis. In agreement with the known action of Akt, blockade of the PI-3K/Akt pathway rendered LNCaP cells highly susceptible to TRAIL. Importantly, active PI-3K/Akt prevented processing/activation of caspase-3, a phenomenon associated with the function of inhibitor of apoptosis proteins (IAPs). In fact, inhibition of PI-3K activity using Wortmannin significantly decreased the protein levels of IAPs, concomitantly promoting processing/activation of caspase-3 and TRAIL-induced apoptosis. My data indicate that in addition to blocking Bad and caspase-9 through Akt, PI-3K also inhibits caspase-3 through up-regulating IAPs, thereby attenuates apoptosis.
Seol
Dai-Wu
DW
Department of Life Science, Kyungwon University, 65 Bokjung-dong, Sujeong-gu, Seongnam-si, Kyeonggi-do 461-701, Republic of Korea; Gachon BioNano Research Institute, Kyungwon University, 65 Bokjung-dong, Sujeong-gu, Seongnam-si, Kyeonggi-do 461-701, Republic of Korea; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: seold@kyungwon.ac.kr.
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D015854:Up-Regulation; D000077191:Wortmannin; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000730:Androstadienes; D053148:Caspase 3; D053453:Caspase 9; D051034:Inhibitor of Apoptosis Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; D051025:bcl-Associated Death Protein